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https://www.readbyqxmd.com/read/28447407/wiedemann-rautenstrauch-syndrome-a-phenotype-analysis
#1
Stefano Paolacci, Debora Bertola, José Franco, Shehla Mohammed, Marco Tartaglia, Bernd Wollnik, Raoul C Hennekam
Wiedemann-Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as "gold standard." In 15 patients sufficient information and photographic evidence was available to confirm the clinical diagnosis. In 12 patients the diagnosis was suggestive but lack of data prevented a definite diagnosis, and in 24 patients an alternative diagnosis was likely...
April 26, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28440507/a-novel-splice-site-mutation-of-wrn-c-ivs28-2t-c-identified-in-a-consanguineous-family-with-werner-syndrome
#2
Pan-Feng Wu, Jie-Yuan Jin, Jing-Jing Li, Ji-Qiang He, Liang-Liang Fan, Min Jin, Hao Huang, Kun Xia, Ju-Yu Tang, Rong Xiang
Werner Syndrome (WS) is a rare, adult‑onset progeroid syndrome that is associated with multiple age‑associated complications and relatively short life expectancy. The characteristics of WS include a 'bird‑like' appearance, canities, cataracts and ulcerations around the ankles. In addition, certain patients develop hypogonadism with atrophic genitalia and infertility. The average life span of affected individuals is 54 years. Previous studies have demonstrated that mutations in the Werner syndrome RecQ like helicase gene (WRN) may contribute to WS...
April 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28423660/progerin-impairs-vascular-smooth-muscle-cell-growth-via-the-dna-damage-response-pathway
#3
Daisuke Kinoshita, Ayako Nagasawa, Ippei Shimizu, Takashi K Ito, Yohko Yoshida, Masanori Tsuchida, Atsushi Iwama, Toshiya Hayano, Tohru Minamino
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK)...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28406750/sirtuins-and-dna-damage-repair-sirt7-comes-to-play
#4
REVIEW
Berta N Vazquez, Joshua K Thackray, Lourdes Serrano
Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7(-/-) mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability...
March 4, 2017: Nucleus
https://www.readbyqxmd.com/read/28394436/recent-trends-in-wrn-gene-mutation-patterns-in-individuals-with-werner-syndrome
#5
Masaya Yamaga, Minoru Takemoto, Aki Takada-Watanabe, Naoko Koizumi, Takumi Kitamoto, Kenichi Sakamoto, Takahiro Ishikawa, Masaya Koshizaka, Yoshiro Maezawa, Koutaro Yokote
OBJECTIVES: To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. DESIGN: Retrospective cohort. SETTING: Longitudinal survey of WS and literature search for case reports. PARTICIPANTS: Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). MEASUREMENTS: A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines...
April 10, 2017: Journal of the American Geriatrics Society
https://www.readbyqxmd.com/read/28383136/age-related-decline-in-bubr1-impairs-adult-hippocampal-neurogenesis
#6
Zhongxi Yang, Heechul Jun, Chan-Ii Choi, Ki Hyun Yoo, Chang Hoon Cho, Syed Mohammed Qasim Hussaini, Ambrosia J Simmons, Seonhee Kim, Jan M van Deursen, Darren J Baker, Mi-Hyeon Jang
Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age-related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain...
April 6, 2017: Aging Cell
https://www.readbyqxmd.com/read/28294978/discriminative-features-in-three-autosomal-recessive-cutis-laxa-syndromes-cutis-laxa-iia-cutis-laxa-iib-and-geroderma-osteoplastica
#7
REVIEW
Ariana Kariminejad, Fariba Afroozan, Bita Bozorgmehr, Alireza Ghanadan, Susan Akbaroghli, Hamid Reza Khorram Khorshid, Faezeh Mojahedi, Aria Setoodeh, Abigail Loh, Yu Xuan Tan, Nathalie Escande-Beillard, Fransiska Malfait, Bruno Reversade, Thatjana Gardeitchik, Eva Morava
Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints...
March 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28276523/homozygosity-for-the-wrn-helicase-inactivating-variant-r834c-does-not-confer-a-werner-syndrome-clinical-phenotype
#8
Ashwini S Kamath-Loeb, Diego G Zavala-van Rankin, Jeny Flores-Morales, Mary J Emond, Julia M Sidorova, Alessandra Carnevale, Maria Del Carmen Cárdenas-Cortés, Thomas H Norwood, Raymond J Monnat, Lawrence A Loeb, Gabriela E Mercado-Celis
Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28229533/expansion-of-myeloid-derived-suppressor-cells-with-aging-in-the-bone-marrow-of-mice-through-a-nf-%C3%AE%C2%BAb-dependent-mechanism
#9
Rafael R Flores, Cheryl L Clauson, Joonseok Cho, Byeong-Chel Lee, Sara J McGowan, Darren J Baker, Laura J Niedernhofer, Paul D Robbins
With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator of the cellular response to damage and stress is the transcription factor NF-κB. We demonstrated previously that NF-κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1-deficient mice). We also demonstrated that genetic reduction in the level of the NF-κB subunit p65(RelA) in the Ercc1(-/∆) progeroid mouse model of accelerated aging delayed the onset of age-related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration...
February 23, 2017: Aging Cell
https://www.readbyqxmd.com/read/28228640/autosomal-dominant-cutis-laxa-with-progeroid-features-due-to-a-novel-de-novo-mutation-in-aldh18a1
#10
Priya T Bhola, Taila Hartley, Eric Bareke, Kym M Boycott, Sarah M Nikkel, David A Dyment
De novo dominant mutations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene have recently been shown to cause autosomal dominant cutis laxa with progeroid features (MIM 616603). To date, all de novo dominant mutations have been found in a single highly conserved amino acid residue at position p.Arg138. We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 (NM_002860.3: c.377G>A (p...
February 23, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28053116/dna-dependent-protease-activity-of-human-spartan-facilitates-replication-of-dna-protein-crosslink-containing-dna
#11
Mónika Mórocz, Eszter Zsigmond, Róbert Tóth, Márton Zs Enyedi, Lajos Pintér, Lajos Haracska
Mutations in SPARTAN are associated with early onset hepatocellular carcinoma and progeroid features. A regulatory function of Spartan has been implicated in DNA damage tolerance pathways such as translesion synthesis, but the exact function of the protein remained unclear. Here, we reveal the role of human Spartan in facilitating replication of DNA-protein crosslink-containing DNA. We found that purified Spartan has a DNA-dependent protease activity degrading certain proteins bound to DNA. In concert, Spartan is required for direct DPC removal in vivo; we also show that the protease Spartan facilitates repair of formaldehyde-induced DNA-protein crosslinks in later phases of replication using the bromodeoxyuridin (BrdU) comet assay...
April 7, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28050601/progeroid-syndrome-patients-with-zmpste24-deficiency-could-benefit-when-treated-with-rapamycin-and-dimethylsulfoxide
#12
Baris Akinci, Shireesha Sankella, Christopher Gilpin, Keiichi Ozono, Abhimanyu Garg, Anil K Agarwal
Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27922816/the-progeroid-gene-bubr1-regulates-axon-myelination-and-motor-function
#13
Chan-Il Choi, Ki Hyun Yoo, Syed Mohammed Qasim Hussaini, Byeong Tak Jeon, John Welby, Haiyun Gan, Isobel A Scarisbrick, Zhiguo Zhang, Darren J Baker, Jan M van Deursen, Moses Rodriguez, Mi-Hyeon Jang
Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant...
September 12, 2016: Aging
https://www.readbyqxmd.com/read/27859906/human-recq-helicase-pathogenic-variants-population-variation-and-missing-diseases
#14
Wenqing Fu, Alessio Ligabue, Kai J Rogers, Joshua M Akey, Raymond J Monnat
Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies...
February 2017: Human Mutation
https://www.readbyqxmd.com/read/27852435/sprtn-is-a-mammalian-dna-binding-metalloprotease-that-resolves-dna-protein-crosslinks
#15
Jaime Lopez-Mosqueda, Karthik Maddi, Stefan Prgomet, Sissy Kalayil, Ivana Marinovic-Terzic, Janos Terzic, Ivan Dikic
Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)- a function that had only been attributed to the metalloprotease Wss1 in budding yeast...
November 17, 2016: ELife
https://www.readbyqxmd.com/read/27799555/cardiac-electrical-defects-in-progeroid-mice-and-hutchinson-gilford-progeria-syndrome-patients-with-nuclear-lamina-alterations
#16
José Rivera-Torres, Conrado J Calvo, Anna Llach, Gabriela Guzmán-Martínez, Ricardo Caballero, Cristina González-Gómez, Luis J Jiménez-Borreguero, Juan A Guadix, Fernando G Osorio, Carlos López-Otín, Adela Herraiz-Martínez, Nuria Cabello, Alex Vallmitjana, Raul Benítez, Leslie B Gordon, José Jalife, José M Pérez-Pomares, Juan Tamargo, Eva Delpón, Leif Hove-Madsen, David Filgueiras-Rama, Vicente Andrés
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24(-/-) mouse model of HGPS. Challenge of Zmpste24(-/-) mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27796797/sublethal-endoplasmic-reticulum-stress-caused-by-the-mutation-of-immunoglobulin-heavy-chain-binding-protein-induces%C3%A2-the-synthesis-of-a-mitochondrial-protein-pyrroline-5-carboxylate-reductase-1
#17
Hisayo Jin, Mari Komita, Haruhiko Koseki, Tomohiko Aoe
Most human neurodegenerative diseases are sporadic and appear later in life. Aging and neurodegeneration are closely associated, and recent investigations reveal that endoplasmic reticulum (ER) stress is involved in the progression of these features. Immunoglobulin heavy chain-binding protein (BiP) is an ER chaperone that is central to ER functions. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence to elucidate the effect of a functional defect in an ER chaperone in multicellular organisms...
January 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/27793082/dwarfism-with-joint-laxity-in-friesian-horses-is-associated-with-a-splice-site-mutation-in-b4galt7
#18
Peter A Leegwater, Manon Vos-Loohuis, Bart J Ducro, Iris J Boegheim, Frank G van Steenbeek, Isaac J Nijman, Glen R Monroe, John W M Bastiaansen, Bert W Dibbits, Leanne H van de Goor, Ids Hellinga, Willem Back, Anouk Schurink
BACKGROUND: Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level...
October 28, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27729169/mutational-and-expressional-alterations-of-zmpste24-dna-damage-response-related-gene-in-gastric-and-colorectal-cancers
#19
Ju Hwa Lee, Nam Jin Yoo, Min Sung Kim, Chang Hyeok An, Sug Hyung Lee
Loss of ZMPSTE24 is related to progeroid phenotypes in human. Cells in zmpste24-deficient mice show delayed DNA damage response, increased aneuploidy and increased genomic instability, which are considered features of cancer cells. The aim of this study was to address whether ZMPSTE24 gene was mutated in colorectal cancers (CRCs) and gastric (GCs), and its expression was altered. ZMPSTE24 possesses a T9 mononucleotide repeat in an exon, which could be mutated in cancers with defects in mismatch repair that can result in microsatellite instability (MSI)...
December 2016: Pathology, Research and Practice
https://www.readbyqxmd.com/read/27667302/wrn-mutation-update-mutation-spectrum-patient-registries-and-translational-prospects
#20
Koutaro Yokote, Sirisak Chanprasert, Lin Lee, Katharina Eirich, Minoru Takemoto, Aki Watanabe, Naoko Koizumi, Davor Lessel, Takayasu Mori, Fuki M Hisama, Paula D Ladd, Brad Angle, Hagit Baris, Kivanc Cefle, Sukru Palanduz, Sukru Ozturk, Antoinette Chateau, Kentaro Deguchi, T K M Easwar, Antonio Federico, Amy Fox, Theresa A Grebe, Beverly Hay, Sheela Nampoothiri, Karen Seiter, Elizabeth Streeten, Raul E Piña-Aguilar, Gemma Poke, Martin Poot, Renata Posmyk, George M Martin, Christian Kubisch, Detlev Schindler, Junko Oshima
Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature...
January 2017: Human Mutation
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